Mechanism of 3-nitropropionic acid-induced membrane permeability transition of isolated mitochondria and its suppression by L-carnitine.
3-Nitropropionic acid (3NP) functions as an irreversible inhibitor of succinic acid dehydrogenase (complex II) and induces neuronal disorders in rats similar to those in patients with Huntington's disease. It is well known that L-carnitine (LC), a carrier of long chain fatty acid into the mitochondrial matrix, attenuates the neuronal degeneration in 3NP-treated rats. From these findings it has been suggested that 3NP induces certain neuronal cell death through mitochondrial dysfunction and that LC preserves the neurons against the dysfunction of mitochondria caused by 3NP. However, the detailed mechanism of cell death by 3NP and the protective actions of LC against the mitochondrial dysfunction have not been fully elucidated yet. Thus, we studied the molecular mechanism of the effects of 3NP and LC on isolated rat liver mitochondria. 3NP inhibited succinate respiration and the decreased respiratory control ratio of isolated mitochondria without affecting oxidative phosphorylation. 3NP induced a membrane permeability transition (MPT), which plays an important role in the mechanism of apoptotic cell death. 3NP stimulated Ca2+ release from mitochondria, decreased membrane potential, induced mitochondrial swelling, and stimulated cytochrome c release from mitochondria. 3NP-induced swelling was suppressed by bovine serum albumin, inhibitors of phospholipase A(2) and by an inhibitor of classic MPT, cyclosporin A. Furthermore, LC suppressed the changes brought about by 3NP in mitochondrial functions in the presence of ATP. These results suggest that MPT underlies the mechanism of 3NP-induced cell death, and that LC attenuates mitochondrial MPT by decreasing long chain fatty acids generated by phospholipase A(2).
Nishimura
Makoto
M
Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Okimura
Yuya
Y
Fujita
Hirofumi
H
Yano
Hiromi
H
Lee
Jintae
J
Suzaki
Etsuko
E
Inoue
Masayasu
M
Utsumi
Kozo
K
Sasaki
Junzo
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002331:Carnitine / Q000494:pharmacology*; D016923:Cell Death; D002463:Cell Membrane Permeability / Q000187:drug effects*; D016572:Cyclosporine / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D009574:Nitro Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000378:metabolism; D010766:Phosphorylation; D011422:Propionates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D019802:Succinic Acid / Q000378:metabolism
D004791:Enzyme Inhibitors; D009574:Nitro Compounds; D064801:Phospholipase A2 Inhibitors; D011422:Propionates; D016572:Cyclosporine; D045304:Cytochromes c; D019802:Succinic Acid; D054467:Phospholipases A2; C015392:3-nitropropionic acid; D002331:Carnitine; D002118:Calcium